1. Field of the Invention
The present invention relates to novel orally active prodrugs of phosphonate nucleotide analogs, their pharmaceutically acceptable acid addition salts, a process for their production, and to their use. The prodrugs of the present invention exhibit antitumor activity and a broad spectrum of antiviral activity.
2. Description of the prior art
Infectious viral diseases are recognized as an important medical problem. Progress against infectious viral diseases requires the development of drugs with selective antiviral activity while remaining benign to normal cell lines. Among the antiviral agents currently under study, which seem to possess selectivity, are phosphonate nucleotide analogs. In general, these compounds are structural analogs of the monophosphates nucleoside analogs.
A number of phosphonate nucleoside analogs have been described in the literature. These nucleoside analogs have been described as potent and selective antiviral agents with activity against a broad spectrum of DNA and RNA viruses.
For example, 9-(3-hydroxy-2-phosphonylmethoxypropyl (HPMP) and (2-phosphonylmethoxy)ethyl (PME) analogs of purine (adenine (A), guanine (G), 2,6-diaminopurine (DAP), 2-monoaminopurine (MAP), hypoxanthine (Hx) and pyrimidine (cytosine (C), uracil (U), thymine (T) were evaluated for antiviral properties. (S)-HPMPA, (S)-cyclic HPMPA, (S)-HPMPC, (S)-HPMPG, (S)-HPMPDAP, PMEDAP, PMEG and PMEA were active against herpes simplex virus, type 1 and 2 (HSV-1 and -2). (S)-HPMPA and (S)-cyclic HPMPA were active against varicella zoster virus (VZV). (S)-HPMPC was active against human cytomegalovirus (HCMV), a common cause of opportunistic infection in AIDS patients. (S)-HPMPA and (S)-cyclic HPMPA are active against adenovirus and vaccinia virus. PMEA, PMEDAP, and PMEMAP are active against human immunodeficiency virus (HIV) the human retrovirus responsible for AIMS. De Clercq, et al, Antiviral Research, 8: 261-272 (1987).
Bronson, et al., report on the series of acyclic nucleotide analogs having a common PME side chain attached to a purine or pyrimidine base which were prepared and selected for in vivo antiviral activity against retroviruses and herpes viruses. The adenine analog, PMEA, showed good in vitro activity against HIV and Rauscher murine leukemia virus (R-MuLV), and was more potent in vivo than 3'-azido-3'-deoxythymidine (AZT) in the treatment of R-MuLV in mice. PMEA also had a significant antiviral effect in vivo against murine cytomegalovirus (MCMV), and in vitro activity against HCMV. The guanine analog, PMEG, was exceptionally potent in vitro against herpes viruses. In vivo, PMEG was &gt;50-fold more potent than acyclovir against HSV 1 infection in mice. Nucleotide Analogs as Antiviral Agents; ACS Symposium Series 401; Martin, J. C. Ed.: Washington, DC, 1989, Chapter 5, pp. 72-87. Kim, et al., in J. Med. Chem., 33: 1207-1213 (1990), describe a similar series of compounds.
De Clercq, et al, in Nature, 323: 464-467. (1986) state that (S)-HPMPA has potent and selective activity against a broad spectrum of DNA viruses, including HSV-1 and 2, VZV, thymidine kinase-deficient (TK.sup.-) mutants of herpes simplex HCMV, phocid herpesvirus type 1 (seal herpesvirus, SeHV), the simian herpesvirus platyrrhinae (HVP), suid herpesvirus type 1 (SHV-1, or pseudorabies virus or Aujeszky's disease virus), bovid herpesvirus type 1 (infectious bovine rhinotracheitis virus, BHV-1), equid herpesviruse type 1 (equine abortion virus, EHV-1), African swine fever (ASF) virus, vaccinia virus; and human adenoviruses, and retroviruses such as murine sarcoma virus (MSV). It is also reported that, in mice and rabbits in vivo, the compound is effective against both local and systemic infections with herpes simplex virus type 1, including herpetic keratitis caused by a TK.sup.- mutant which is resistant to the classical anti-herpes drugs.
European Patent Application 205,826, to De Clercq, et al, published Dec. 30, 1986, discloses that HPMPA analogs are active against Moloney mouse sarcoma virus, and are expected to be effective against retroviruses in general.
Reist and Sturm in U.S. Pat. No. 84/00737, published Dec. 6, 1984 disclosed new phosphonic acid analogs of nucleoside phosphates which are useful as antivirals for incorporation into viral DNA.
Adenine phosphonic acid analogs and their synthesis are disclosed in the United Kingdom Patent application of Holy, et al., GB 2,134,907A, published on Aug. 22, 1984, and its related U.S. Pat. No. 4,659,825. A preferred example of one of these compounds, is known as (S)-9-((3-hydroxy-2-phosphonylmethoxy)propyl)adenine (HPMPA). HPMPA was disclosed by E. DeClercq, et al., in Nature, 323: 464-467, (1986), in Antiviral Research, 8: 261-272, (1987), and earlier by A. Holy, et al., Nucleic Acids Research, Symposium Series No. 14: 277-278, (1984).
Phosphonylmethoxyalkylpurine analogs have also been evaluated for their antitumor activity in murine tumor models. HPMPA, PMEA, and PMEG were found to be active against intraperitoneal P388 leukemia. PMEG was also found to be active against B16 melanoma. Rose, et al, J. of the Nat. Cancer Inst., Vol. 82, No. 6 (1990).
A problem with nucleotides and other ionic organophosphate esters is their inability to traverse biological membranes. Liebman, et al, J. Biol. Chem., 216: 823 (1955); Roll, et al, J. Biol. Chem., 220: 439 (1956). These compounds must, therefore, be given parenterally in order to achieve adequate serum levels to exert an antiviral effect.
Parenteral treatment is highly undesirable, especially with HIV infected patients. With HIV infected patients oral treatment is preferred since (i) HIV infected patients are very ill and need to be on chronic chemotherapy programs to maintain their health; (ii) the risk of using needle stick and presence of blood is high for health workers; (iii) disposal of infected needles is a problem; and (iv) the need for long-term maintenance therapy.
The inventors of this invention have carried out studies in order to circumvent the above-mentioned problem. The present application, thus, relates to the preparation and use of a number of oral prodrugs of phosphonate nucleotide analogs.
In J. Med. Chem, 32:1457-1463 (1989), Bronson et al., disclose the synthesis of HPMPC wherein the following compound is disclosed as an intermediate ##STR1##
In Nucleotide Analogs as Antiviral Agents, ACS Symposium Series 401, J. C. Martin, Ed., p. 72, American Chemical Society, Washington, D.C. (989), Bronson et al., disclose the synthesis of phosphonylmethoxy ether derivatives wherein the following compound was disclosed as an intermediate ##STR2## wherein R is ethyl or isopropyl.
European Patent Application EP-270,885 of Webb, et al., published Jun. 15, 1988 discloses a process for the preparation of purin-9-ylalkylenoxymethyl phosphonic acids, wherein several intermediates are produced in the practice of the process. One such intermediate is dialkylphosphonylmethyl which has the general structural formula ##STR3## wherein R.sup.1 and R.sup.2 independently are selected from C.sub.1-6 alkyl.
European Patent Application EP 253,412 of Holy, et al., published Jan. 20, 1988, discloses the preparation of a series of N-phosphonylmethoxyalkyl derivatives of pyrimidine and purine bases exhibiting antiviral activity, wherein in the practice of the process,. several intermediates are produced. One such intermediate has the general structural formula ##STR4##
European Patent Application EP-269,947 of R. R. Webb, II, et al., published on Jun. 8, 1988, discloses a series antiviral agents which are phosphonomethoxyalkylene purine and pyrimidine derivatives having the following general structure ##STR5## wherein R.sup.3 and R.sup.4 are independently selected from hydrogen, C.sub.1-6 alkyl, phenyl and phenyl-C.sub.1-4 -alkylene.
The art compounds are generally distinguished from the compounds of the instant invention by the nature of the groups attached to the phosphorous atom. There is no disclosure or suggestion in the above references, or combination thereof, which would make obvious the use of a suitably protected phosphonate derivative prodrug for oral use.